Characterization of the Genomic Breakpoint in t(11:18)(q21:q21) of MALT Lymphoma

Reviewer: Ryan Smith, MD
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Last Modified: December 8, 2002

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Presenter: Hongxiang LiuPresenter's Affiliation: University College LondonType of Session: Scientific

Background

The t(11:18)(q21:q21) is the most frequent chromosomal aberration found in mucosa associated lymphoid tissue (MALT) lymphoma. This translocation fuses the API2 gene to the MALT 1 gene, generating a functional fusion transcript. However, the exact breakpoints of the two separate genes and the fusion point is poorly understood, and the mechanism underlying the translocation are unknown. The aim of this study was to understand these molecular mechanisms in t(11:18)(q21:q21) of MALT lymphoma.

Materials and Methods

22 cases of t(11:18)(q21:q21) MALT lymphoma were identified, of which, 19 cases were successfully amplified for the API2-MALT1 fusions

The tissues were analyzed to determine the breakpoints and DNA anomalies within the genes.

Results

The breakpoint in the API2 gene was found to be in either intron 7 (16 cases) or exon 8 (3 cases). However, the exact breakpoint within these were variable, with each case having a unique breakpoint

The breakpoint in the MALT1 gene were in introns 4, 6, 7, and 8, with only 1 repeat exact breakpoint

4 cases had variable insertions on both genes, 9 cases had variable deletions on both genes, 1 case had DNA duplications on both genes, and 3 cases had deletions on one gene and duplications on the other gene. Hence, there was extensive modifications of genes prior to joining

There were no specific recombination signals noted

Other DNA motifs (octomers, binding sites, etc.) were found at low frequencies

The Alu repeat was found to span the breakpoints in 37% of cases

Author's Conclusions

Breakpoints for the API2 gene and ther MALT1 gene were scattered randomly, with no specific repeating breakpoint able to be identified

The translocation almost always involved insertions, deletions or duplications, but at no specific sequence

These observations lend proof to the fact that the t(11:18)(q21:q21) translocation may result from both homologous recombination and non-homologous end joining to result in the API2-MALT1 fusion gene found in many MALT cases.

Clinical/Scientific Implications

The API2-MALT1 fusion is the sole consistent chromosomal aberration found in MALT. It is found in 40% of MALT cases and is associated with advanced stages of disease and H. pylori negative disease. If the specific breakpoint could be identified, the diagnosis and treatment of MALT could be advanced. The specific API2-MALT1 gene could be screened for or targeted for therapy. Unfortunately, from the results of this study, the gene product is highly variable. With this information known, further investigation into common sequences could be done, perhaps elucidating insight into this complex disease.

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